Treatment for end-stage renal disease (ESRD) with hemodialysis, the most common renal replacement modality, is currently aimed at clearing urea. Hemodialysis patients continue to experience high rates of morbidity and mortality far in excess of the general population. The recent HEMO clinical trial revealed that enhanced urea clearance did not lead to improved mortality. There are a large number of organic solutes, other than urea, that are retained in ESRD. Many of these solutes have characteristics, such as protein-binding or sequestration in certain body compartments, which do not allow them to be cleared efficiently through current dialysis methods. It is currently unknown whether these solutes are associated with the poor outcomes experienced by dialysis patients. The overall goal of this application is to identify retained solutes which are associated with poor outcomes in hemodialysis patients. The study design will be a cohort study in which biological specimens have been obtained and stored. These stored specimens will be retrieved, analyzed for levels of putative toxins and correlated with important patient outcomes. We propose to take advantage of the large specimen repositories available in the CHOICE and HEMO studies, as well as the prior work to carefully characterize patients and their outcomes, to test hypotheses that particular kidney failure solutes (e.g. p-cresol sulfate, indoxyl sulfate, methylamine) are associated with poor dialysis outcomes. CHOICE is a prospective cohort study of 767 incident hemodialysis patients recruited from 1995-1998 and HEMO is a prospective, multicenter, randomized clinical trial in which 1846 participants were recruited between 1995 and 2000. Both these studies have specimen banks containing frozen specimens from baseline and annual follow-ups which we propose to assay for organic solutes. We will relate levels of these organic solutes to all-cause mortality, cardiovascular events, loss of appetite, low albumin levels, restless leg symptoms and self reported problems with cognition. The application will build a collaboration of experienced programs in the clinical and laboratory sciences to address a fundamental issue in the science of kidney failure and its treatment. This study will have important implications for understanding the cause of the substantial morbidity and mortality in ESRD patients and the development of future interventions to address these causes, thereby seeking to improve the quality and length of life for ESRD patients. The application will build a collaboration of experienced programs in the clinical and laboratory sciences to address a fundamental issue in the science of kidney failure and its treatment. This study will have important implications for understanding the cause of the substantial morbidity and mortality in chronic kidney disease patients and the development of future interventions to address these causes, thereby seeking to improve the quality and length of life for persons with chronic kidney disease. The proposal will build a collaboration of experienced programs in the clinical and laboratory sciences to address a fundamental issue in the science of kidney failure and its treatment. This study will have important implications for understanding the cause of the substantial morbidity and mortality in chronic kidney disease patients and the development of future interventions to address these causes, thereby seeking to improve the quality and length of life for persons with chronic kidney disease.